Wisconsin Scientists Assemble Puzzle of Red Blood Cell Genes

For the first time, scientists have pieced together a complete picture of all the genes involved in the formation of red blood cells, and the way the genes work with key proteins. The work by researchers at the University of Wisconsin School of Medicine and Public Health (UW SMPH) should have implications for understanding and ultimatley treating leukemia as well as anemias associated with aging, infection and genetic mutations.

Like much of what goes on in our bodies, most of us take cellular activity for granted. Not so, for Emery Bresnick, PhD, a UW SMPH professor of pharmacology and hematology/oncology medicine, and an expert on proteins in blood. The complex genetic picture Bresnick and his team have assembled includes. Their findings, reported in the Nov. 25, 2009, issue of Molecular Cell, also describe the GATA-2 protein that controls blood stem cells and red blood cell development and interacts with many of the same genes, as well as other genes bound only by GATA-2.

Bresnick knows that for red blood cells to develop, these thousands of genes must work smoothly together, turning on and off at precisely the right time. Proteins, specifically GATA proteins 1 and 2, create this genetic network and keep it running correctly.

Too few red blood cells can lead to dangerous anemias, affecting elderly people, cancer patients on chemotherapy and those with sickle cell anemia. Err in the other direction, and too many red blood cell precursors can lead to leukemia.

While earlier studies have revealed some of the genes involved in this network, Bresnick and his collaborators have completed the picture using a living cell. The new findings include genes that turn other genes on and off, signaling molecules and proteins that are the structural building blocks of red blood cells.

The findings are an important step in understanding how red blood cells are formed in a highly complex and dynamic process directed by GATA factors. Focusing on one cluster of red blood cell genes associated with leukemia in mice, the researchers identified a pathway that may be important in understanding the disease in humans.

“It has been very challenging until now to understand how the network functions because important pieces of the puzzle have been missing,” Bresnick says. “Establishing the complete ensemble reveals a rich collection of targets for inluencing blood cell development and function. The next step is to determine how genes and GATA factors connect and function together in the epigenome. That will help us understand whether and how to intervene when something goes wrong in the genetic network.”